Phenothiazine tfflocarboxyiates



UniteddStates Patent PHENOTHMZINE THIOCARBOXYLATES Arthur W. Weston, Waukegan, 111., assignor to Abbott Laboratories, North Chicago, 111., acorporation of Elinois No Drawing. Filed Jan. 16, 1956, Ser. No. 559,096 4 Claims. or. 260-243) The present invention relates to a new class of organic compounds and more particularly to the phenothrazine thiocarboxylates of the following structural formula and the salts thereof, wherein R is an alkylene group containing from 2 to 4 carbon atoms and -NR R is a member ofthe class consisting of dialkylamino and nitrogen containing heterocyclic radicals which are attached to the alkylene group through the nitrogen atom.

The compound-s of' this invention possess anti-spasmodic properties and antihistaminic properties. bases represented herein are useful as intermediate in the preparation of the salts also described in the application.

qThe alkylenegroup designated above by the symbol R 'includes such radicals as ethylene, propylene, butylene and the branch chain equivalents thereof containing not more than 4 carbon atoms.

The radical -NR R includes such dialkylamino radicals as may have lower alkyl groups containing up to 4 carbon atoms inclusive, and may also represent such heterocyclic radicals as the piperidinyl, pyrrolidinyl, N- rnethyl pipera'zinyl and morpholinyl' radicals.

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The following examples are given in order to more clearly disclose the nature of the present invention. It should be understood, however, that the examples are not intended to be a limitation on the scope of the invention.

EXAMPLE I fl-Diethylaminoethyl phenothiazine-IO-thiocarboxylate A mixture of about 12.3 grams of phenothiazine-IO- carboxylic acid chloride and 13.3 grams (0.1 mol) of B-diethylaminoethyl mercaptan are boiled in anhydrous benzene for 24 hours. The reaction mixture is shaken with water and then the benzene layer isextracted with dilute hydrochloric acid. The acid layer is treated with a 40% potassium hydroxide solution and the oil thus formed is extracted with ether. The ethereal solutionis dried over magnesium sulfate. A little dry benzene is added and the solvents are removed under reduced pressure. The semi-solid residue-is boiled with pentane until all of the soluble material has been dissolved. The hot solution is shaken with charcoal, filtered, concentrated, I and cooled in ice. The base, fi-diethylaminoethyl phenothiazine-10-thiocarboxylate, crystallizes from said solution. The base may then be recrystallized trom petroleum ether if desired;

The hydrochloride salt is prepared by gassing the above base dissolved in ethanol with hydrogen chloride gas and The term salts as used herein is intended to include all non-toxic or pharmacologically acceptable salts of the basic compounds, including both the acid addition salts and the quaternary ammonium salts.

' The organic bases of the foregoing type' fornrsalts' with a variety of inorganic and strong organic acids including:

sulfuric, phosphoric, hydrochloric, hydrobromic, sulfarnic, citric, oxalic, ascorbic and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl clhloride, benzyl chloride and bromide; phenethyl bromide, naphthylrnethyl chloride, dimethyl sulfate, di-

ethyl sulfate, methyl benzencsulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The compounds of this invention are preferably prepared by a reaction between a phenothiazine-lO-carboxylic acid halide and an -NR R alkylmercaptan where NR R is as previously defined. The reaction is usually carried out in an inert solvent of the hydrocarbon type such as benzene. The acid addition salts may be suitably prepared directly from the reaction mixture by acidifying with dilute acid such as hydrochloric acid. The alkyl halide quaternary salts are suitably prepared by treating the base in an anhydrous solvent medium with an excess of the alkyl halide and recrystallizing the product from ethanol.

recrystallizing from an ethanol-ether mixture; fi-Diethylaminoethyl phenothiazine-l O-thiocarboxylate hydrochloride is obtained melting at l187-198 C.

EXAMPLE l-I B-Diethylaminoethyl pherwthiazine-IO-thiocdrboxylate methiodide A solution of the base of Example Iis dissolved in dry ether and is added to a other solution of methyl iodide in an amount in excess of the stoichiometric amount, and

Crystal- 1 the mixture is allowed to stand for two hours. line ,B-diethylaminoethyl phenothiazine-lO-thiocarboxylate methiodide is obtained and has -a melting point of 230-231. C. with decomposition. The analysis is C, 47.93; H, 4.94; N, 5.70 as compared to the calculated C, 48.0; H, 5.03; N, 5.59.

. By a similar process p-diethylaminoethyl phenothiazine-l'O-thiocarboxylate methobromide is obtained having a melting point of 228" C. with decomposition. The

nitrogen analysis is 5.96 as compared to a calculated 6.18. EXAMPLE in [3-Dimethylamin0ethyl phenothiazine-IO-thiocarboxylate EXAMPLE IV fl-Diethylaminoisopropyl phenothiazr'ne-10- thiocarboxylate Employing the process of Example I, 12.3 grams of phenothiazine-lO-carboxylic acid chloride is reacted with 14.7 grams (0.1 mol) of fi-diethylaminoisopropyl mercaptan and the resulting base is purified and converted to the hydrochloride by the indicated method. Crystalline B-diethylaminoisopropyl phenothiazine-lO-thiocarboxylate hydrochloride is recovered from the reaction mixture.

aaaaera 3 EXAMPLE v B-Diethylaminopropyl phenothiazz'rte-lO-thiocarboxylate Q Employing the process of Example I, 26.1 grams (0.1 mol) of phenothiazine-lO-carboxylic acid chloride is reacted with 29.4 grams (0.2 mol) of fi-diethylaminopropyl mercaptan and the resulting base, fi-diethylaminopropyl phenothiazine--thiocarboxylate is converted to the hydr-obromide salt which crystallizes from solvent medium.

EXAMPLE VI fl-Pyrrolidylethyl phenothiazine-lO-thiocwrboxylate Employing the process of Example I, 13 grams of phenothiazine-lO-carboxylic acid chloride is reacted with 13.1 grams (0.1 mol) of fi-pyrrolidylethylrnercaptan. The resulting base, 'fi-py-rrolidylethyl phenothiazine-IO- thiocarboxylate, is converted to the hdyrochloride salt by the indicated method and the salt is recrystallized from alcoholic solution EXAMPLE vn fl-Piperidylethyl phenothiazine-IO-thiocarboxylate Employing the process of Example I, 24.5 grams of phenothiazine-10-carboxylic acid chloride is reacted with 36 grams (0.25 mol) of fi-piperidylethyl mercaptan and the resulting base, fi-piperidylethyl phenothiazine-lO-thiocarboxylate, is converted to the hydrochloride salt by the indicated method. The salt precipitates from an alcoholic medium.

EXAMPLE VIII B-Dibutylamirwethyl phenothiazine-lO-thiocarboxylate Employing the process of Example I, 26.1 grams of phenothiazinedO-carboxylic acid chloride is reacted with 16.1 grams of fi-diethylaminobutyl mercaptan and the resulting base, .fi-diethylaminobutyl phenothiazine-lO-thiocarboxylate, is converted to the hydrochloride salt by the indicated method.

4 EXAMPLE X fl-Zllorpholinylethyl phenothiazine-lO-thiocarboxylate Employing the process of Example I, 26.1 grams of phenothiazine-IO-carboxylic acid chloride is reacted with 14.7 grams of 8-morpholinylethyl mercaptan and the resulting base, li-morpholinylethyl phenothiazine-10-thiocarboxyl-ate, is converted to the hydrochloride salt which crystallizes from solvent medium.

This application is a continuation-impart of application Serial No. 247,749, now abandoned, filed September 21, 1951.

Others may practice the invention in any of the numerous ways which will be suggested to one skilled in the art upon a reading of this disclosure. All such practice of the invention is intended to be included herewith provided it falls within the scope of the appended claims.

I claim:

. 1. A compound selected from thegroup consisting of bases of the formula the non-toxic lower alkyl halide quaternary salts and the non-toxic acid addition salts thereof, wherein R is an alkylene group containing from 2 to 4 carbon atoms inclusive, and --NR R is a member selected from the group consisting of diloweralkylamino, piperidyl, pyrrolidyl, N-methylpiperazinyl and morpholinyl groups.

2. B-Diethylaminoethyl pehnothiazine-lO-thiocarboxylate. 1

3. B-Diethylaminoethyl phenothiazine-lO-thiocarboxylate hydrochloride.

4. fl-Diethylaminoethyl phenothiazine-lO-thiocarboxylate methiodide.

References Cited in the file of this patent UNITED STATES PATENTS 2,650,919 Cusic Sept. 1, 1953 FOREIGN PATENTS 514,330 Belgium Oct. 15, 1952 OTHER, REFERENCES Dahlbom et al.: Acta Pharmacol. et Toxicol, vol. 9, pp. 168-178,(1953).

Dahlbom, Acta Chem. Scand., vol. VII, pp. 879-884 1953 v 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA 